Oral cancer is one of the 10 most frequent cancers worldwide, with an estimated 30,000 new cases being diagnosed in the U.S. every year. Histologically almost 90 percent of oral cancers are squamous cell carcinomas (SCC), which include the subtypes of verrucous carcinoma and basaloid squamous cell carcinoma. There is increasing evidence to suggest that local invasion and regional/distant metastasis of carcinomas are facilitated by increased expression and altered subcellular localization of lysosomal cathepsins B, D and L. The Hypothesis of this proposal is: Oral carcinomas with different local invasive properties and metastatic potentials possess distinct qualitative and quantitative differences in their expression patterns of cathepsin B, D and L. The inhibition of such cathepsins on the molecular level will diminish, or abolish, these malignant properties. The Specific Aims of the proposal are: Specific Aim 1: To determine the relationship of the expression patterns of cathepsins B, D, and L in oral carcinomas and their clinicopathologic parameters and histological characteristics. Specific Aim 2: To inhibit cathepsin expression in oral squamous cell carcinoma cell lines by intracellularly expressed ribozymes, and to analyze the consequences on invasive and metastatic behavior of these cells in an animal model. Specific Aim 3: To obtain overexpression of selected cathepsin proteins in transformed keratinocytes cells, and to test for induction of acquired invasive and/or metastatic phenotypes in these cells in an animal model. These experiments are designed to correlate the expression patterns of cathepsin B, D, L in oral cancer with the histological characteristics and clinical findings of the carcinoma subtypes. These studies will also examine the role of these enzymes in invasion and metastasis by employing ribozyme- mediated cathepsin inhibition as well as recombinant cathepsin gene expression approaches, both being applied in cell culture and in an animal model. The information correlating the functions of cathepsins B, D and L in oral cancer progression will be the basis for the design of therapeutic modalities to inhibit their expression, and thus cancer progression, on the molecular level.